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Mol Cell Biol. Nov 1996; 16(11): 6486–6493.
PMCID: PMC231650

A structural basis for substrate specificities of protein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1.

Abstract

We have developed a method to study the primary sequence specificities of protein kinases by using an oriented degenerate peptide library. We report here the substrate specificities of eight protein Ser/Thr kinases. All of the kinases studied selected distinct optimal substrates. The identified substrate specificities of these kinases, together with known crystal structures of protein kinase A, CDK2, Erk2, twitchin, and casein kinase I, provide a structural basis for the substrate recognition of protein Ser/Thr kinases. In particular, the specific selection of amino acids at the +1 and -3 positions to the substrate serine/threonine can be rationalized on the basis of sequences of protein kinases. The identification of optimal peptide substrates of CDK5, casein kinases I and II, NIMA, calmodulin-dependent kinases, Erk1, and phosphorylase kinase makes it possible to predict the potential in vivo targets of these kinases.

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Selected References

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  • Adam LP, Hathaway DR. Identification of mitogen-activated protein kinase phosphorylation sequences in mammalian h-Caldesmon. FEBS Lett. 1993 May 3;322(1):56–60. [PubMed]
  • Brattsand G, Marklund U, Nylander K, Roos G, Gullberg M. Cell-cycle-regulated phosphorylation of oncoprotein 18 on Ser16, Ser25 and Ser38. Eur J Biochem. 1994 Mar 1;220(2):359–368. [PubMed]
  • Cheng JT, Cobb MH, Baer R. Phosphorylation of the TAL1 oncoprotein by the extracellular-signal-regulated protein kinase ERK1. Mol Cell Biol. 1993 Feb;13(2):801–808. [PMC free article] [PubMed]
  • De Bondt HL, Rosenblatt J, Jancarik J, Jones HD, Morgan DO, Kim SH. Crystal structure of cyclin-dependent kinase 2. Nature. 1993 Jun 17;363(6430):595–602. [PubMed]
  • Flotow H, Graves PR, Wang AQ, Fiol CJ, Roeske RW, Roach PJ. Phosphate groups as substrate determinants for casein kinase I action. J Biol Chem. 1990 Aug 25;265(24):14264–14269. [PubMed]
  • Gonzalez FA, Raden DL, Davis RJ. Identification of substrate recognition determinants for human ERK1 and ERK2 protein kinases. J Biol Chem. 1991 Nov 25;266(33):22159–22163. [PubMed]
  • Hanks SK, Quinn AM. Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol. 1991;200:38–62. [PubMed]
  • Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988 Jul 1;241(4861):42–52. [PubMed]
  • Haycock JW, Ahn NG, Cobb MH, Krebs EG. ERK1 and ERK2, two microtubule-associated protein 2 kinases, mediate the phosphorylation of tyrosine hydroxylase at serine-31 in situ. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2365–2369. [PMC free article] [PubMed]
  • Hu SH, Parker MW, Lei JY, Wilce MC, Benian GM, Kemp BE. Insights into autoregulation from the crystal structure of twitchin kinase. Nature. 1994 Jun 16;369(6481):581–584. [PubMed]
  • Hubbard SR, Wei L, Ellis L, Hendrickson WA. Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature. 1994 Dec 22;372(6508):746–754. [PubMed]
  • Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massagué J, Pavletich NP. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature. 1995 Jul 27;376(6538):313–320. [PubMed]
  • Knighton DR, Zheng JH, Ten Eyck LF, Xuong NH, Taylor SS, Sowadski JM. Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science. 1991 Jul 26;253(5018):414–420. [PubMed]
  • Kuenzel EA, Mulligan JA, Sommercorn J, Krebs EG. Substrate specificity determinants for casein kinase II as deduced from studies with synthetic peptides. J Biol Chem. 1987 Jul 5;262(19):9136–9140. [PubMed]
  • Lu KP, Kemp BE, Means AR. Identification of substrate specificity determinants for the cell cycle-regulated NIMA protein kinase. J Biol Chem. 1994 Mar 4;269(9):6603–6607. [PubMed]
  • Osmani AH, McGuire SL, Osmani SA. Parallel activation of the NIMA and p34cdc2 cell cycle-regulated protein kinases is required to initiate mitosis in A. nidulans. Cell. 1991 Oct 18;67(2):283–291. [PubMed]
  • Pearson RB, Kemp BE. Protein kinase phosphorylation site sequences and consensus specificity motifs: tabulations. Methods Enzymol. 1991;200:62–81. [PubMed]
  • Resing KA, Mansour SJ, Hermann AS, Johnson RS, Candia JM, Fukasawa K, Vande Woude GF, Ahn NG. Determination of v-Mos-catalyzed phosphorylation sites and autophosphorylation sites on MAP kinase kinase by ESI/MS. Biochemistry. 1995 Feb 28;34(8):2610–2620. [PubMed]
  • Shetty KT, Link WT, Pant HC. cdc2-like kinase from rat spinal cord specifically phosphorylates KSPXK motifs in neurofilament proteins: isolation and characterization. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6844–6848. [PMC free article] [PubMed]
  • Solomon MJ, Harper JW, Shuttleworth J. CAK, the p34cdc2 activating kinase, contains a protein identical or closely related to p40MO15. EMBO J. 1993 Aug;12(8):3133–3142. [PMC free article] [PubMed]
  • Songyang Z, Blechner S, Hoagland N, Hoekstra MF, Piwnica-Worms H, Cantley LC. Use of an oriented peptide library to determine the optimal substrates of protein kinases. Curr Biol. 1994 Nov 1;4(11):973–982. [PubMed]
  • Williams R, Sanghera J, Wu F, Carbonaro-Hall D, Campbell DL, Warburton D, Pelech S, Hall F. Identification of a human epidermal growth factor receptor-associated protein kinase as a new member of the mitogen-activated protein kinase/extracellular signal-regulated protein kinase family. J Biol Chem. 1993 Aug 25;268(24):18213–18217. [PubMed]
  • Xu RM, Carmel G, Sweet RM, Kuret J, Cheng X. Crystal structure of casein kinase-1, a phosphate-directed protein kinase. EMBO J. 1995 Mar 1;14(5):1015–1023. [PMC free article] [PubMed]
  • Yuan CJ, Huang CY, Graves DJ. Phosphorylase kinase, a metal ion-dependent dual specificity kinase. J Biol Chem. 1993 Aug 25;268(24):17683–17686. [PubMed]
  • Zhang F, Strand A, Robbins D, Cobb MH, Goldsmith EJ. Atomic structure of the MAP kinase ERK2 at 2.3 A resolution. Nature. 1994 Feb 24;367(6465):704–711. [PubMed]

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